ArticleThe Journal of biological chemistry2006
Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner.
Article in The Journal of biological chemistry, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers.
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Who cites it
115 citing papers in PubMed, 161 citations in OpenAlex.
- Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide.Journal of translational medicine · 2012Trial
- The MLLT3 YEATS domain binds histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking transcription and RNA signaling to regulate hematopoiesis.Cell reports · 2026Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- The MLLT3 YEATS domain is a dual reader of histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking epigenetic and RNA signaling to regulate hematopoiesis.bioRxiv : the preprint server for biology · 2025Article
- Development of Chemical Tools for the Human YEATS Domain.ACS chemical biology · 2025Review
- An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system.Frontiers in immunology · 2024Review
- Aldosterone: Renal Action and Physiological Effects.Comprehensive Physiology · 2023Article
- BMP4 drives primed to naïve transition through PGC-like state.Nature communications · 2022Article
- DOT1L inhibition enhances pluripotency beyond acquisition of epithelial identity and without immediate suppression of the somatic transcriptome.Stem cell reports · 2022Article
- The Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer.Journal of molecular biology · 2022Review
- Serum and glucocorticoid-regulated kinase 1: Structure, biological functions, and its inhibitors.Frontiers in pharmacology · 2022Review
- Protein Methylation in Diabetic Kidney Disease.Frontiers in medicine · 2022Review
- Transcription Pause and Escape in Neurodevelopmental Disorders.Frontiers in neuroscience · 2022Review
- The Role and Mechanism of Lysine Methyltransferase and Arginine Methyltransferase in Kidney Diseases.Frontiers in pharmacology · 2022Review
- Article
- Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation.EMBO reports · 2021Article
- CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis.International journal of molecular sciences · 2020Article
- Loss of Histone H3 K79 Methyltransferase Dot1l Facilitates Kidney Fibrosis by Upregulating Endothelin 1 through Histone Deacetylase 2.Journal of the American Society of Nephrology : JASN · 2020Article
- Characterization of Copy Number Variations in Oral Cavity Squamous Cell Carcinoma Reveals a Novel Role for MLLT3 in Cell Invasiveness.The oncologist · 2019Article
- Epigenetic synthetic lethality approaches in cancer therapy.Clinical epigenetics · 2019Review
55 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Aldosterone is a major regulator of epithelial Na(+) absorption and acts in large part through induction of the epithelial Na(+) channel (ENaC) gene in the renal collecting duct. We previously identified Dot1a as an aldosterone early repressed gene and a repressor of ENaCalpha transcription through mediating histone H3 Lys-79 methylation associated with the ENaCalpha promoter. Here, we report a novel aldosterone-signaling network involving AF9, Dot1a, and ENaCalpha. AF9 and Dot1a interact in vitro and in vivo as evidenced in multiple assays and colocalize in the nuclei of mIMCD3 renal collecting duct cells. Overexpression of AF9 results in hypermethylation of histone H3 Lys-79 at the endogenous ENaCalpha promoter at most, but not all subregions examined, repression of endogenous ENaCalpha mRNA expression and acts synergistically with Dot1a to inhibit ENaCalpha promoter-luciferase constructs. In contrast, RNA interference-mediated knockdown of AF9 causes the opposite effects. Chromatin immunoprecipitation assays reveal that overexpressed FLAG-AF9, endogenous AF9, and Dot1a are each associated with the ENaCalpha promoter. Aldosterone negatively regulates AF9 expression at both mRNA and protein levels. Thus, Dot1a-AF9 modulates histone H3 Lys-79 methylation at the ENaCalpha promoter and represses ENaCalpha transcription in an aldosterone-sensitive manner. This mechanism appears to be more broadly applicable to other aldosterone-regulated genes because overexpression of AF9 alone or in combination with Dot1a inhibited mRNA levels of three other known aldosterone-inducible genes in mIMCD3 cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.